Protein phosphorylation is a fundamental process for the regulation of cellular functions. The coordinated action of both protein kinases and phosphatases controls the levels of phosphorylation and, hence, the activity of specific target proteins. One of the predominant roles of protein phosphorylation is in signal transduction, where extracellular signals are amplified and propagated by a cascade of protein phosphorylation and dephosphorylation events.
While a plethora of extracellular molecules exist that modulate cellular functions via binding to membrane receptors inside the cell, their actions are mediated by relatively few signaling mechanisms within the cell. One of these mechanisms is activation of phosphatidylinositol 3-kinase (PI-3K), which results in the generation of membrane-restricted second messenger polyphosphatidyl-inositides containing a 3′-phosphate, and the activation of protein kinase B (PKB). Activated PKB induces NF-κB (Kane et al. (1999) Curr Biol 1999 June 3;9(11):601–4); mediates a number of metabolic effects of insulin; and protects cells from apoptosis.
Most proliferating cells are programmed to undergo apoptosis unless specific survival signals are provided. Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/threonine kinase PKB, which then phosphorylates and inactivates components of the apoptotic machinery. Survival factor withdrawal triggers apoptosis by inducing the expression of genes that are critical for cell death.
Signal transduction also plays a key regulatory role in the growth and metastatic potential of tumor cells. These signaling pathways form an interconnecting grid that serves to regulate the homeostatic, survival and invasive functions of the cell. Among the key regulatory molecules in these pathways are the serine/threonine-protein kinases cyclic AMP-dependent protein kinase (PKA), Akt (PKB) and protein kinase C (PKC). These protein kinases modulate pathways associated with tumor proliferation, cell survival and multidrug resistance, and at a molecule level are likely to serve as effective targets for drug design.